. 2023 Mar 6;32(3):315-328.

doi: 10.1158/1055-9965.EPI-22-0763.

Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Robert Carreras-Torres^#^{1

2

3}, Andre E Kim^#⁴, Yi Lin⁵, Virginia Díez-Obrero^{1

2

6}, Stephanie A Bien⁵, Conghui Qu⁵, Jun Wang⁴, Niki Dimou⁷, Elom K Aglago⁷, Demetrius Albanes⁸, Volker Arndt⁹, James W Baurley¹⁰, Sonja I Berndt⁸, Stéphane Bézieau¹¹, D Timothy Bishop¹², Emmanouil Bouras¹³, Hermann Brenner^{9

14

15}, Arif Budiarto¹⁰, Peter T Campbell¹⁶, Graham Casey¹⁷, Andrew T Chan¹⁸, Jenny Chang-Claude¹⁹, Xuechen Chen⁹, David V Conti⁴, Christopher H Dampier²⁰, Matthew A M Devall¹⁷, David A Drew²¹, Jane C Figueiredo²², Steven Gallinger²³, Graham G Giles²⁴, Stephen B Gruber²⁵, Andrea Gsur²⁶, Marc J Gunter⁷, Tabitha A Harrison⁵, Akihisa Hidaka⁵, Michael Hoffmeister⁹, Jeroen R Huyghe⁵, Mark A Jenkins²⁷, Kristina M Jordahl⁵, Eric Kawaguchi⁴, Temitope O Keku²⁸, Anshul Kundaje²⁹, Loic Le Marchand³⁰, Juan Pablo Lewinger⁴, Li Li³¹, Bharuno Mahesworo¹⁰, John L Morrison⁴, Neil Murphy⁷, Hongmei Nan³², Rami Nassir³³, Polly A Newcomb⁵, Mireia Obón-Santacana^{1

2

6}, Shuji Ogino^{34

35

36

37}, Jennifer Ose^{38

39}, Rish K Pai⁴⁰, Julie R Palmer⁴¹, Nikos Papadimitriou⁷, Bens Pardamean¹⁰, Anita R Peoples³⁸, Paul D P Pharoah⁴², Elizabeth A Platz⁴³, Gad Rennert⁴⁴, Edward Ruiz-Narvaez⁴⁵, Lori C Sakoda⁴⁶, Peter C Scacheri⁴⁷, Stephanie L Schmit^{48

49}, Robert E Schoen⁵⁰, Anna Shcherbina⁵¹, Martha L Slattery⁵², Mariana C Stern⁴, Yu-Ru Su⁵, Catherine M Tangen⁵³, Duncan C Thomas⁴, Yu Tian^{19

54}, Konstantinos K Tsilidis^{55

13}, Cornelia M Ulrich^{38

39}, Fränzel J B van Duijnhoven⁵⁶, Bethany Van Guelpen^{57

58}, Kala Visvanathan⁴³, Pavel Vodicka⁵⁹, Tjeng Wawan Cenggoro¹⁰, Stephanie J Weinstein⁸, Emily White⁵, Alicja Wolk⁶⁰, Michael O Woods⁶¹, Li Hsu⁵, Ulrike Peters^{5

62}, Victor Moreno^{1

2

6

63}, W James Gauderman⁴

Affiliations

¹ Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
² Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
³ Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, Girona, Spain.
⁴ Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California.
⁵ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
⁶ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁷ Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
⁸ Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.
⁹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
¹¹ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
¹² Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
¹³ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
¹⁴ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁵ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
¹⁷ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.
¹⁸ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
¹⁹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Department of General Surgery, University of Virginia School of Medicine, Charlottesville, Virginia.
²¹ Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
²² Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
²³ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
²⁴ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
²⁵ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, California.
²⁶ Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
²⁷ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
²⁸ Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina.
²⁹ Department of Genetics, Department of Computer Science, Stanford University, Stanford, California.
³⁰ University of Hawaii Cancer Center, Honolulu, Hawaii.
³¹ Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
³² Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, Indiana.
³³ Department of Pathology, School of Medicine, Umm Al-Qura'a University, Saudi Arabia.
³⁴ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
³⁵ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
³⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
³⁷ Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
³⁸ Huntsman Cancer Institute, Salt Lake City, Utah.
³⁹ Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
⁴⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona.
⁴¹ Slone Epidemiology Center at Boston University, Boston, Massachusetts.
⁴² Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
⁴³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
⁴⁴ Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
⁴⁵ Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan.
⁴⁶ Division of Research, Kaiser Permanente Northern California, Oakland, California.
⁴⁷ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio.
⁴⁸ Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio.
⁴⁹ Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, Ohio.
⁵⁰ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
⁵¹ Biomedical Informatics Program, Dept. of Biomedical Data Sciences, Stanford University, Stanford, California.
⁵² Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
⁵³ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
⁵⁴ School of Public Health, Capital Medical University, Beijing, P.R. China.
⁵⁵ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
⁵⁶ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands.
⁵⁷ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
⁵⁸ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
⁵⁹ Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, and Biomedical Center, Medical Faculty, Pilsen, Czech Republic.
⁶⁰ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁶¹ Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada.
⁶² School of Public Health, University of Washington, Seattle, Washington.
⁶³ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.

^# Contributed equally.

PMID: 36576985
PMCID: PMC9992283
DOI: 10.1158/1055-9965.EPI-22-0763

Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Robert Carreras-Torres et al. Cancer Epidemiol Biomarkers Prev. 2023.

. 2023 Mar 6;32(3):315-328.

doi: 10.1158/1055-9965.EPI-22-0763.

Authors

Affiliations

¹ Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
² Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
³ Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, Girona, Spain.
⁴ Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California.
⁵ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
⁶ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁷ Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
⁸ Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.
⁹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
¹¹ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
¹² Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
¹³ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
¹⁴ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁵ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
¹⁷ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.
¹⁸ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
¹⁹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Department of General Surgery, University of Virginia School of Medicine, Charlottesville, Virginia.
²¹ Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
²² Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
²³ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
²⁴ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
²⁵ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, California.
²⁶ Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
²⁷ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
²⁸ Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina.
²⁹ Department of Genetics, Department of Computer Science, Stanford University, Stanford, California.
³⁰ University of Hawaii Cancer Center, Honolulu, Hawaii.
³¹ Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
³² Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, Indiana.
³³ Department of Pathology, School of Medicine, Umm Al-Qura'a University, Saudi Arabia.
³⁴ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
³⁵ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
³⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
³⁷ Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
³⁸ Huntsman Cancer Institute, Salt Lake City, Utah.
³⁹ Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
⁴⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona.
⁴¹ Slone Epidemiology Center at Boston University, Boston, Massachusetts.
⁴² Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
⁴³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
⁴⁴ Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
⁴⁵ Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan.
⁴⁶ Division of Research, Kaiser Permanente Northern California, Oakland, California.
⁴⁷ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio.
⁴⁸ Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio.
⁴⁹ Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, Ohio.
⁵⁰ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
⁵¹ Biomedical Informatics Program, Dept. of Biomedical Data Sciences, Stanford University, Stanford, California.
⁵² Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
⁵³ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
⁵⁴ School of Public Health, Capital Medical University, Beijing, P.R. China.
⁵⁵ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
⁵⁶ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands.
⁵⁷ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
⁵⁸ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
⁵⁹ Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, and Biomedical Center, Medical Faculty, Pilsen, Czech Republic.
⁶⁰ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁶¹ Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada.
⁶² School of Public Health, University of Washington, Seattle, Washington.
⁶³ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.

^# Contributed equally.

PMID: 36576985
PMCID: PMC9992283
DOI: 10.1158/1055-9965.EPI-22-0763

Abstract

Background: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer.

Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia.

Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33).

Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response.

Impact: These findings can guide potential prevention treatments.

PubMed Disclaimer

Conflict of interest statement

The authors declare no potential conflicts of interest.

Figures

**Figure 1-**
Association parameters of smoking habits for colorectal cancer risk in the overall sample and stratified by sex and tumour site.

**Figure 2-**
Manhattan plots for the standard interaction tests of smoking habits for colorectal cancer risk. A: Smoking status (ever vs never smokers). B: Cigarettes smoked per day. C: Pack-years.

**Figure 3-**
Association parameters of smoking habits for colorectal cancer risk stratified by genotypes.

**Figure 4-**
Association parameters of genetically predicted gene expression for colorectal cancer risk stratified by smoking status.

See this image and copyright information in PMC

References

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Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Affiliations

Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Miscellaneous